DESCRIPTION: Most therapy for glaucoma is directed at the management of the intraocular pressure (IOP). Conventional wisdom holds that excessive pressure within the eye leads to the ganglion cell loss/optic nerve damage seen in this disease. The data presented in this application, however, suggest that toxic levels of glutamate can contribute to glaucomatous visual loss. Both glutamate and elevated IOP can selectively damage the retinal ganglion cells of the optic nerve. The PI has identified an 2-3 fold elevation of glutamate in the vitreous of glaucoma patients. In the monkey model of laser-induced glaucoma, the elevation is even higher (to 5-7 times the control values). The PI has established that a 2-3 fold elevation of glutamate in the rat vitreous--when sustained for an extended period of time--can lead to the loss of retinal ganglion cells in a pattern that is very similar to that seen in human glaucoma. Therefore, even if the elevation of glutamate he has observed is simply a byproduct of the neuronal damage-- the concentration of glutamate he has found in glaucomatous vitreous is sufficient on its own to cause ganglion cell loss. In this grant proposal, he will investigate the following hypotheses: (1) The central hypothesis is that glutamate is elevated in the vitreous of glaucoma patients. Analysis of additional primate (human and monkey) samples may help in identifying whether the glaucoma diagnosis, or anti-glaucoma therapy plays a role in glutamate elevation. (2) He hypothesizes that the excess glutamate arises from the retina, either from ganglion or Muller cells. (3) If glutamate toxicity plays a role in glaucomatous loss, then drugs that can block glutamate damage may be effective in controlling glaucomatous blindness. (3A) He will first evaluate glutamate antagonists in a model of chronic glutamate toxicity. (3B) If these drugs are successful at blocking chronic glutamate toxicity, then (if glutamate toxicity is important in glaucoma) these agents should also retard glaucomatous loss. The PI will therefore test these drugs in a rat glaucoma model. These experiments will help test the central hypothesis--for if one can block the effects of IOP elevation with glutamate antagonists, then elevated IOP may toxic glutamate levels ganglion cell loss.